Hironobu Akao

Genetic variation at the SLCO1B1 gene locus and low density lipoprotein cholesterol lowering response to pravastatin in the elderly.

Our goal was to determine whether genetic variation at genes affecting statin metabolism or targets of statin therapy would influence low density lipoprotein (LDL) cholesterol lowering with pravastatin, baseline heart disease, or cardiac endpoints on trial. We examined associations of single nucleotide polymorphisms (SNPs) at the liver X receptor alpha (LXRA, rs12221497), and the solute carrier organic anion transporter (SLCO1B1, rs4149056 and rs2306283) gene loci with these variables. We studied 5411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. No relationships between genetic variation at the LXRA gene locus with statin induced LDL lowering response or other parameters were noted. Both the SLCO1B1 rs4149056 (valine for alanine at 174) and the rs2306283 (asparagine for aspartic acid at 130) SNPs affect the amino acid sequence of the SLCO1B1 gene product. No effect of the rs2306283 SNP on any of the variables was noted. However the presence of the rs4149056 SNP was associated with significantly less LDL cholesterol lowering response to pravastatin (wildtype, 71.5% of the population, -37.0%; heterozygotes, 25.8% of the population, -36.0%; and homozygotes, 2.7% of the population, -31.8%, p=0.003 at 6 months, and p=0.022 at 12 months). Our data indicate that the presence of the rs4149056 non-synonymous SNP at the SLCO1B1 gene locus can significantly decrease the pravastatin induced LDL cholesterol lowering response.

KIF6, LPA, TAS2R50, and VAMP8 genetic variation, low density lipoprotein cholesterol lowering response to pravastatin, and heart disease risk reduction in the elderly.

Single nucleotide polymorphisms (SNPs) at the KIF6 (kinesin like protein 6, rs20455 or 719Arg), LPA (lipoprotein(a), rs3798220), TAS2R50 (taste receptor type 2, member 50, rs1376251) and VAMP8 (vesicle-associated membrane protein 8, rs1010) have previously been associated with low density lipoprotein cholesterol (LDL-C) lowering response to statins, coronary heart disease (CHD) at baseline, or CHD events on trial. We examined SNPs at the KIF6 (rs20455 or 719Arg), LPA (rs3798220), TAS2R50 (rs1376251) and VAMP8 (rs1010) in 5,411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. No SNP was related to vascular disease at baseline. Only the KIF6 SNP was related to LDL-C lowering with homozygous Arg 719 subjects being significantly less responsive than other groups (p=0.025, -34.2 vs. -36.1%). With regard to the primary CHD endpoint on trial (fatal or non-fatal myocardial infarction or stroke), we observed a significant relationship for KIF6 719Arg homozygotes (p=0.03, hazards ratio 0.47, 12.8% of the population) in women on pravastatin only, and for TAS2R50 for the AA genotype (p=0.03, hazards ratio 1.76, 8.9% of the population), also only in women on pravastatin. Our data indicate that the assessment of KIF6 rs20455 and TAS2R50 rs1376251 genotypes are not useful for predicting statin induced cardiovascular risk reduction in men, but do predict CHD risk reduction in women in this elderly population. However, these differences are no longer significant after correction for multiple comparisons, and we do not recommend the assessment of any of these SNPs in clinical practice.

Increased levels of the oxidative stress marker, nitrotyrosine in patients with provocation test-induced coronary vasospasm

BACKGROUND Endothelial dysfunction of the coronary arteries caused by oxidative stress plays an important role in the pathogenesis of coronary vasospasm. However, it is not clear whether circulating biomarkers for oxidative stress are altered after coronary vasospasm. We investigated temporal changes in the levels of oxidative stress biomarkers after coronary vasospasm induced by intracoronary acetylcholine provocation testing, resulting in transient myocardial ischemia. METHODS AND RESULTS Thirty consecutive patients with suspected vasospastic angina pectoris (VSAP) were enrolled in the study. Patients were categorized into the VSAP-positive group (n=14) and the VSAP-negative group (n=16) on the basis of test results. Serum samples were examined for the levels of the oxidative stress markers 4-hydroxynonenal (HNE) and nitrotyrosine (NT) before, and 15min, 3h, and 12h after the provocation test. The serum HNE levels did not change in either group after the test. The serum NT levels in the VSAP-positive group significantly increased at 3h and 12h after the test (11.3±3.3μg/ml at 3h, p=0.015, and 12.1±5.7μg/ml at 12h, p=0.03), as compared with baseline (8.1±3.2μg/ml). In the VSAP-negative group, the serum NT levels significantly decreased from baseline at each of the 3 time points. CONCLUSIONS Serum NT significantly increased after coronary vasospasm induced by acetylcholine provocation, suggesting that serum NT could be a biomarker of transient myocardial ischemia and could contribute to the development of VSAP.

A case of coronary rupture and pseudoaneurysm formation after fracture of implanted paclitaxel-eluting stents

A 48-year-old man who had undergone implantation of two paclitaxel-eluting stents (PESs) at the right coronary artery was admitted to our hospital with progressive dyspnea. In the coronary care unit, he developed cardiogenic shock due to cardiac tamponade treated by pericardiocentesis. A coronary angiogram showed a large pseudoaneurysm at the site of the previously implanted stents, suggesting coronary rupture due to implanted stent fracture. The pseudoaneurysm was completely sealed by polytetrafluoroethylene-covered stent implantation. Although this case is very rare, coronary rupture by stent fracture should be considered when cardiac tamponade occurs after drug-eluting stent implantation, especially PES.

ABCA1 gene variation and heart disease risk reduction in the elderly during pravastatin treatment

AIMS Our goals were to examine the relationships of a specific ATP-binding cassette transporter A1 (ABCA1) variant, rs2230806 (R219K), on baseline lipids, low-density lipoprotein cholesterol (LDL-C) lowering due to pravastatin, baseline heart disease, and cardiac endpoints on trial. METHODS AND RESULTS The ABCA1 R219K variant was assessed in 5414 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and followed for a mean of 3.2 years. Of these subjects 47.6% carried the variant, with 40.0% carrying one allele, and 7.6% carrying both alleles. No effects on baseline LDL-C levels were noted, but mean HDL-C increased modestly according to the number of variant alleles being present (1.27 vs 1.28 vs 1.30 mmol/L, p = 0.024). No relationships between the presence or absence of this variant and statin induced LDL-C lowering response or CHD at baseline were noted. However within trial those with the variant as compared to those without the variant, the overall adjusted hazard ratio for new cardiovascular disease (fatal CHD, non-fatal myocardial infarction, or fatal or non-fatal stroke) was 1.22 (95% CI 1.06-1.40, p = 0.006), while for those in the pravastatin group it was 1.41 (1.15-1.73, p = 0.001), and for those in the placebo group it was 1.08 (0.89-1.30, p = 0.447) (p for interaction 0.058). CONCLUSION Our data indicate that subjects with the ABCA1 R219K variant may get significantly less heart disease risk reduction from pravastatin treatment than those without the variant.

Chronic total occlusions of the right coronary and left anterior descending coronary arteries in a young adult patient with antiphospholipid syndrome

A 36-year-old male appeared to have an old myocardial infarction on electrocardiogram, and coronary angiography (CAG) was performed. The CAG showed total occlusions of the right coronary artery and left anterior descending artery. He was successfully treated with drug-eluting stent implantation for both occluded coronary arteries. Such serious coronary lesions are uncommon for his young age. The patient was diagnosed as having antiphospholipid syndrome (APS) based on elevation of anticardiolipin antibody and anti-β2 glycoprotein I antibody. Two years after stent implantation, the patient was well without ischemia or thrombosis. APS should be considered a potential cause of serious coronary disease in young adults. <Learning objective: Antiphospholipid syndrome (APS) should be considered a potential cause of serious coronary disease in young adults. Although there is a high risk of acute stent thrombosis and restenosis after multiple stents implantation, percutaneous coronary intervention with drug-eluting stent implantation could be an appropriate therapy for chronic total occlusion in APS patients.>.

Probucol: Can we step forward in atherosclerosis prevention with an old drug?

Atherosclerosis is associated with increased inflammation and xidative stress. This leads to the hypothesis that an agent with nti-inflammatory and anti-oxidative activities might have the otential of being athero-protective. Probucol is a di-phenolic ipid-lowering prototype agent with such properties, that might e expected to be useful in atherosclerosis prevention. Since its ntroduction as a cholesterol-lowering drug nearly 40 years ago 1], probucol has received considerable interest, but with mixed cceptance. In addition to many experimental studies, early clinical tudies provided both disappointing and promising results [2–5]. owever, two negative characteristics of probucol, the lowering f high-density lipoprotein cholesterol (HDL-C) and the cardiac lectrophysiological influence of QT prolongation, resulted in its ery limited use in clinical practice. This was also because of he world-wide spread of statin use as a first-line cholesterolowering therapy. As a result, the holders of its patent, Hoechst arion Roussel, decided on the voluntary withdraw of the drug rom the US market in 1995, and after that, the clinical use of robucol has been limited to only a few countries, including apan. In the previous issue of the Journal, the long-term effects of robucol therapy following coronary revascularization have been nvestigated using an observational study design and propensity nalysis [6]. In this study from a single center in Japan, Dr. Kasai nd coworkers collected data from 1694 consecutive patients who nderwent complete revascularization (percutaneous catheter ntervention and/or bypass surgery). Mortality data were compared etween patients who at the time of revascularization were either